DESCRIPTION: (Applicant's Abstract) Liproprotein lipase (LPL) plays a crucial role in the distribution of plasma triglyceride fatty acids to different tissues. Abnormalities in LPL function are, therefore, suspected to be implicated in a variety of lipid related diseases in humans. Familial LPL deficiency, when untreated, is characterized by fasting hyperchylomicronemia, severe abdominal pain, splenomegaly, hepatomegaly, eruptive xanthomas and pancreatitis. The French-Canadian population in Quebec is found to have the largest group of LPL deficient individuals in the world, with the number of carriers estimated to be as high as 1 in 40 in certain regions. In Quebec patients, LPL deficiency is an autosomal recessive disorder resulting from different mutations in the coding sequence of the LPL gene. Proband distribution studies indicate that mutation P207L which is the major cause of LPL deficiency in Quebec is almost exclusively French-Canadian. LPL is present in variable concentrations in different regions of the nervous system, although the brain tissue, as a whole, is not as rich in LPL as the adipose tissue and muscle. Considering the central position of LPL in lipid metabolism, it appears very likely that it may have an important and special function in brain, a tissue which depends critically on lipoproteins and essential fatty acids for its structure and function. In view of the practical and ethical constraints in the availability of inaccessible human tissues, particularly brain, we plan to investigate the role of LPL in the nervous system by using a mouse model of LPL deficiency (cld/cld) in combination with studies of the blood cells of LPL deficient human patients. We hope to answer the following questions: (a) Does lipoprotein lipase deficiency lead to structural and/or functional alterations in the brain cells of experimental animals? (b) Are these alterations in brain reflected in corresponding parameters in the circulating lymphocytes and platelets? (c) Can these animal data be used to identify possible markers of abnormal brain function in the lymphocytes and platelets of human subjects suffering from familial LPL deficiency? The structural parameters to be examined will include membrane composition of lipids, liproproteins and fatty acids as well as membrane fluidity. The functional parameters will include synaptosomal and platelet uptake of serotonin and the expression, in the brain cells and in lymphocytes, of certain selected genes involved in the metabolism of neurotransmitters and in the formation of neuropeptides and brain specific proteins.